Scale-Up and Post-Approval Changes (SUPACs)
A. Purpose
These guidelines are intended to reduce the number of manufacturing changes that require preapproval by the FDA. The guidelines are published by the FDA.
B. Function
These guidelines provide recommendations to sponsors of NDAs, AADAs, and ANDAs during the postapproval period when:
- making slight changes in the amount of the excipient to aid in the processing of the product during scale-up,
- changing the site of manufacture,
- scaling up (increasing) or scaling down (decreasing) the batch size of the formulation, and
- changing the manufacturing process or equipment.
C. The FDA must be notified about a proposed change to a drug product through different regulatory documentation, depending on the type of change proposed.
1. Annual report
Changes that are unlikely to have any detectable effect on formulation quality and performance can be instituted without approval by the FDA and reported annually. Examples of these changes include the following:
- Compliance with an official compendium
- Label description of the drug product or how it is supplied (not involving dosage strength or dosage form)
- Deletion of an ingredient that affects only the color of the product
- Extension of the expiration date based on full shelf-life data obtained from a protocol approved in the application
- Container and closure system for the drug product (except a change in container size for nonsolid dosage forms) based on equivalency to the approved system under a protocol approved in the application or published in an official compendium
- Addition or deletion of an alternate analytical method
2. Changes being effected (CBE) supplement
Changes that probably would not have any detectable effect but require some validation efforts require specific documentation, depending on the change. A supplement is submitted, and the change can be implemented without previous approval ( CBE-0) by the FDA or, in some cases, the FDA has 30 days to review the change ( CBE-30). The FDA may reject this supplement. Examples of reasons for submitting a supplement include the following:
- Addition of a new specification or test method or changes in methods, facilities, or controls
- Label change to add or strengthen a contraindication, warning, precaution, or adverse reaction
- Use of a different facility to manufacture the drug substance and drug product (the manufacturing process in the new facility does not differ materially from that in the former facility, and the new facility has received a satisfactory cGMP inspection within the previous 2 years covering that manufacturing process)
3. Preapproval supplement
Changes that could have a significant effect on formulation quality and performance require specific documentation. This supplement must be approved before the proposed change is initiated. Appropriate examples for preapproval supplement are the following:
- Addition or deletion of an ingredient
- Relaxation of the limits for a specification
- Establishment of a new regulatory analytical method
- Deletion of a specification or regulatory analytical method
- Change in the method of manufacture of the drug product, including changing or relaxing an in-process control
- Extension of the expiration date of the drug product based on data obtained under a new or revised stability testing protocol that was approved in the application
D. When any change to a drug product is proposed, the manufacturer must show that the resultant drug product is bioequivalent and therapeutically equivalent to the original approved drug product
1. A minor change is a change that has minimal potential to have an adverse effect on the identity, strength, quality, purity, or potency of the product as they may relate to the safety or effectiveness of the product. If the proposed change is considered minor by the FDA, bioequivalence may be demonstrated by comparative dissolution profiles for the original and new formulations.
2. A major change is one that has substantial potential to have an adverse effect on the identity, strength, quality, purity, or potency of a product as they may relate to the safety or effectiveness of the product. If the proposed change is considered major by the FDA, bioequivalence must be demonstrated by an in vivo bioequivalence study comparing the original and new formulations.
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